1-oxa-a-nor-steroids

ABSTRACT

1-Oxa-13 Beta -R1-17 Alpha -methyl-A-nor- Delta 3(5),9gonadienes of the formula   WHEREIN R1 is alkyl of one to three carbon atoms and R2 is acyl of an aliphatic carboxylic acid of two to four carbon atoms having antiandrogenic activity and their preparation and intermediates formed therein.

United States Patent Muller et al. [45] July 11, 1972 [54]l-OXA-A-NOR-STEROIDS Primary Examiner-Alex Maze! Assistant Examiner-AnneMarie T. Tighe [72] Inventors: Georges Muller, Nogent sur Marne; Ro-Anomey flammond & L n

land Bardoneschi, le Vert Galant, both of France [57] ABSTRACT [73]Assignee: Roussel UcLaf, Paris, France l-Oxa-l3,B-R,-l7a-methyl-A-nor-A-gonadienes of the for- 221 Filed: July 7, 1969 R l 21 Appl. No.:839,706 0R2 cm [30] Foreign Application Priority Data July 24, 1968France ..l60425 [52] US. Cl. ..260/343.3, 260/247.7 A, 260/293.65,

260/326.5 C, 260/348 C, 260/563 P, 260/586 A, wherein R is alkyl of oneto three carbon atoms and R is acyi 424/279 of an aliphatic carboxylicacid of two to four carbon atoms [5 1 1 Int. Cl. having anfland ogenicactivity and their preparation and inter- [58] Field of Search..260/343.3 mediates formed therein.

[56] References Cited 8 Claims No D wings UNITED STATES PATENTSl-OXA-A-NOR-STEROIDS STATE OF THE ART There are known 2-oxa-A"-dienesteroids such as 2-oxal7B-acetoxy-A -estradiene-3-one which possessanabolic and androgenic activity. In copending, commonly assigned U.S.Pat. application Ser. No. 839659, filed on even date herewith, there aredisclosed 1-oxa-A-nor-A --estradiene-l7fl-ol-2- one and esters andethers thereof which possess antiandrogenic activity. The compounds ofthe present invention maintain antiandrogenic activity even with thel7a-methyl group and presence of the acyl group in the l7B-position prolongs the activity of the compounds when taken orally.

OBJECTS OF THE INVENTION It is an object of the invention to providel-oxa-l 7a-methyll7B-OR,-A-nor-steroids of formula I.

It is another object of the invention to provide a process for thepreparation of the compounds of formula I and to novel intermediatesproduced therein.

It is a further object of the invention to provide antiandrogeniccompositions.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION The compounds of the invention are l-oxa-l3fl-R,-l7fl- OR-l7a-methyl-A-nor-A --gonadienes of the formula wherein R, is alkyl ofone to three carbon atoms, and R and R may be different and are alkyl ofone to six carbon atoms together with the nitrogen atom to which theyare attached form a substituted or unsubstituted heterocyclic radicalwhich may contain an oxygen atom with a lower aliphatic carboxylic acidto form the corresponding l3B-R,-l 7a-methyl-des-A-M-gonene-l7B-ol-5'one of the formula III reacting the latter with anepoxidation agent to obtain the corresponding 9fi,l0fl-epoxy-l3B-R,-l7a-methyl-des-A-gonancl7fl-ol-5-one of the formula reacting thelatter with a lower alkyl haloacetate in the presence of zinc to form aSfl-alkoxycarbonylmethyl-9B,IOB-epoxy-l3B-R,-l7oz-methyl-des-A-gonane-5a,l7B-diol of the formula whereinX is chlorine or bromine and reacting the latter with an aliphatic acidanhydride of two to four carbon atoms in the presence of an organictertiary base to form the desired compound of formula I.

In preferred embodiments of the invention, the enamino is piperidino,morpholino or pyrrolidino and the lower aliphatic carboxylic acid isdilute propionic acid or acetic acid. The epoxidation agent is hydrogenperoxide in an alkaline alcoholic media. The lower alkyl haloacetate ispreferably methyl or ethyl bromoacetate, methyl or ethyl chloroacetateor methyl or ethyl iodoacetate. The tertiary organic base is pyridine orcollidine.

The S-enamino starting materials of formula II may be prepared by theprocess of commonly assigned, copending U.S. Pat. application Ser. No.752,467, filed Aug. 14, 1968,, now U.S. Pat. No. 3,595,877 whichcomprises oxidizing 13B- R,-des-A-A-gonene-l7B-ol-5-one wherein R, hasthe above definition to form l3fi-R,-des-A-A-gonene-5,l7-dionc, reactingthe latter with a secondary amine of the formula /NH R wherein R and Rhave the above definition and reacting the latter with a methylatingagent such as methyl lithium or a methyl magnesium halide to form thecorresponding 5- enamino of formula II.

5 -Pyrrolidinol 3 fi-n-propyl-l 7 B-benzoyloxy-des-A- A "-gonadiene(described in U.S. Pat. No. 3,115,507) may be saponiiied to thecorresponding 173 01 compound which can then be oxidized to thecorresponding l7-0ne which can be reacted with methyl lithium to obtainS-pyrrolidino-l 3 B-n-propyll 7a-methyl-des-A-A gonadiene-l 73-01.

The antiandrogenic compositions comprise at least one compound offormula 1 a pharmaceutical carrier. The compositions may be in the formof injectable solutions or suspensions in ampules or multiple-doseflacons or in the form of tablets, coated tablets, capsules, sublingualtablets, suppositories, pomades, creams or lotions prepared in knownways. They are useful for the treatment of hyperandrogenia or acne.

1n the following example there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE Preparation of l-oxal 7a-methyl-l 7fl-acetoxy-A-nor-Aestradiene-2-one STEP A: l 7a-methyl-des-A-A-estraenel 7fi-ol-5-one 72.5gm of S-pyrrolidino-l7a-methyl-des-A-A "-estradiene- 1 713-01 (describedin copending US. Pat. application Ser. No. 752,467) were dissolved in130 cc pure acetic acid and 1,250 cc of water and the solution wasstirred overnight at room temperature. The reaction mixture was madealkaline by the addition of 1,150 cc of 2N sodium hydroxide and was thenextracted with methylene chloride. The organic phase was washed withwater, then with hydrochloric acid then with water, dried over sodiumsulfate and distilled to dryness at a temperature less than 40 C. Theresidue was purified by trimrating with isopropyl ether to obtain 43.1gm of raw 17amethyl-des-A-A -estraene-17B-ol-5-one melting at 113-1l4 CFor analysis, the product was purified by chromatography and triturationwith isopropyl ether to obtain the product having a melting point of 125C. and a specific rotation [at] I) 55.2 (c= 0.5 percent in methanol).STEP B: 9B,10B-epoxy-l 7a-methyl-des-A-estrane-l 73-01-5- one 5 gm of17a-methyl-des-A-A -estraene-17B-ol-5-one were dissolved in 50 cc ofpure anhydrous methanol and after cooling to 5 C., 1 cc of 36 Be sodiumhydroxide solution and then 5 cc of 30 percent hydrogen peroxide wereadded thereto. The reaction mixture was stirred at 5 C. for 5 hours andthen was poured into water and extracted with methylene chloride. Theextract was washed with water, dried and distilled in vacuo. The residuewas recrystallized from a mixture of isopropyl ether-methylene chlorideto obtain 3.14 gm of 9B,10Bepoxy- 17a-methyl-des-A-estrane-l7B-ol-5-onehaving a melting point of 139 C. and a specific rotation [at] D=l 22: 3(c 0.5 percent in chloroform).

Analysis: c..H,,0,; Calculated: C 71.97% Found: 71.9

As far as is known, this compound is not described in the literature.STEP C: 5-ethoxycarbonylmethyl-9B, l OB-epoxy-l7a-methyldes-A-estrane-5a,l7fl-diol 1 gm of 9fi,l0fl-epoxyl7a-methyl-des-A-estrane-l 7B-ol-5- one was dissolved in 30 cc ofanhydrous tetrahydrofuran and then 30 cc of an 0.8 M solution of thezinc derivative of ethyl bromoacetate in methylal was added thereto. Thereaction mixture was stirred at room temperature for 1 hour and then waspoured into ice water. The mixture was acidified with 2 N hydrochloricacid and was then extracted with ether. The ether extract was washedwith water, dried and distilled to dryness. The residue consisted of5B-ethoxycarbonylmethyl-9B,lOB-epoxy-l7a-methyl-des-A-estrane-5a,17B-diol which was used as isfor the next synthesis step.

As far as is known, this compound is not described in the literature.STEP D: l-oxa-9a-chloro-l 7a-methyl-A-nor- 1 Oa-estrane-5a,l7B-diol-2-one Analysis: C H,,O.Cl; Calculated: C 62.09% Found: 61.8

molecular weight 328.83 H 7.66% CI 10.78%

As far as is known, this compound is not described in the literature.

STEP E: l-oxa-l 7a-methyl-l7B-acetoxy-A-nor-A --estradiene-2-one.

980 mg of l-oxa-9a-chloro-l7a-methyl-A-nor-lOa-estrane-5a,l7B-diol-2-one were introduced into a mixture of 16 cc of pyridineand 4 cc of acetic acid anhydride and the mixture was then refluxedunder a nitrogen atmosphere for 5 hours. After cooling, 4 cc of waterwere added to the reaction mixture and after the reaction was over, themixture was poured over ice. The pH was adjusted to l by the addition of2 N hydrochloric acid and the mixture was then extracted with methylenechloride. The organic extracts were washed with water, then with anaqueous solution of sodium bicarbonate, dried and distilled to dryness.The residue was dissolved in methylene chloride and the solution waschromatographed over alumina with elution with methylene chloride. Thesolution was distilled to dryness and the residue was recrystallizedfrom ether to obtain 385 mg of l-oxa-l7a-methyl-l7B-acetoxy-A- nor-A-estradiene-2-one melting at 208 C. A sample of the said product uponrecrystallization from a mixture of methylene chloride and isopropylether had a melting point of 210 C. and a specific rotation [a] D -58 t2 (c 0.40 percent in chloroform).

Analysis: C l-l m; Calculated: C 72.12%

Found:

As far as is known, this compound is not described in the literature.

Various modifications of the compositions and process of the inventionmay be made without departing from the spirit or scope thereof.

We claim:

1. A l-oxa-13fi-R,-l7a-methyl-A-nor-A --gonadiene of the formula whereinR is alkyl of one to three carbon atoms, and R and R may be ditferentand are alkyl of one to six carbon atoms and together with the nitrogenatom to which they are attached form a member selected from the groupconsisting of pyrrolidino, piperidino and morpholino with a loweralkanoic carboxylic acid to form the corresponding l3fl-R-l7amethyl-desA-M-gonenel 7fl-ol-5-one of the formula lll reacting thelatter with an epoxidation agent to obtain the corresponding9B,1OB-epoxy-l3B-R -lla-methyl-des-A-gonanel7B-0l-5-one of the formula fon reacting the latter with a lower alkyl haloacetate in the presence ofzinc to form a SB-alkoxycarbonylmethyl-Qfl,10B- epoxy-l3B-R -l7a-methyl-des-A-gonane-5a,17B-diol of the formula wherein R is loweralkyl, treating the latter with a hydrogen halide to form thecorresponding l-oxa-Qa-halo-l 7rr-mcthyl-A-nor-lOa-gonanc-SBJ7fi-diol-2-onc ofthc formula ll Vl wherein X ischlorine or bromine and reacting the latter with an alkanoic acidanhydride of two to four carbon atoms in the presence of an organictertiary base to form the desired compound of claim 1.

4. A process of claim 3 wherein the group methyl and ethyl iodoacetate.

7. compound of the formula wherein R is alkyl of one to three carbonatoms and X is a halogen.

8. A compound of claim 7 which is l-oxa-9a-chloro-l7amethyl-A-norlOa-estrane-Sa, l 7B-diol-2-one.

2. A compound of claim 1 wherein R1 is methyl and R2 is acetyl.
 3. Aprocess for the preparation of a compound of claim 1 which comprisesreacting a 5-enamino-13 Beta -R1-17 Alpha -methyl-des-A- Delta5,(10),9(11)-gonadiene-17 Beta -ol of the formula
 4. A process of claim3 wherein the group is selected from the group consisting of piperidino,morpholino and pyrrolidino.
 5. The process of claim 3 wherein theepoxidation agent is hydrogen peroxide in an alkaline alcoholic media.6. The process of claim 3 wherein the lower alkyl haloacetate isselected from the group consisting of methyl and ethyl bromoacetate,methyl and ethyl chloroacetate and methyl and ethyl iodoacetate.
 7. Acompound of the formula
 8. A compound of claim 7 which is 1-oxa-9 Alpha-chloro-17 Alpha -methyl-A-nor-10 Alpha -estrane-5 Alpha ,17 Beta-diol-2-one.